CA2477720C - Quinoline derivatives - Google Patents
Quinoline derivatives Download PDFInfo
- Publication number
- CA2477720C CA2477720C CA2477720A CA2477720A CA2477720C CA 2477720 C CA2477720 C CA 2477720C CA 2477720 A CA2477720 A CA 2477720A CA 2477720 A CA2477720 A CA 2477720A CA 2477720 C CA2477720 C CA 2477720C
- Authority
- CA
- Canada
- Prior art keywords
- compound
- formula
- acid addition
- glaucoma
- salt form
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 C*1C(SC[C@](C2)CN(C)[C@](C3)C2Cc2c3cccc2O)=NC=C1 Chemical compound C*1C(SC[C@](C2)CN(C)[C@](C3)C2Cc2c3cccc2O)=NC=C1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Ophthalmology & Optometry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The present invention relates to a compound of formula I, its preparation and its use as a pharmaceutical in the treatment of glaucoma or myopia; the compound of formula I being:
(see formula I) wherein the CH2-S-imidazol substituent in formula I presents the configuration 3R, in free base or acid addition salt form.
(see formula I) wherein the CH2-S-imidazol substituent in formula I presents the configuration 3R, in free base or acid addition salt form.
Description
Quinoline Derivatives The present invention relates to novel benzo ~g~ quinoline derivatives, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
The present present invention pertains to a compound selected from the group consisting of compound of formula la, R
N-CH3 Ia HO_ ~ ~ H
Wherein A and Q are each H or form together an additional bond, and wherein the asymmetric center in position 3 may be racemic, or in form of an optically active form, and wherein R is of formula Ib or Ic, N ~ N~R1 Ib S N Ic N
and wherein R1 is alkyl, in free base or acid addition salt form.
In a preferred aspect A and Q are each H. In a further preferred aspect A and Q form together an additional bond.
The substituent CH2-R in position 3 of formula la is preferably in configuration 3R, provided A and Q are each H.
R1 is preferably selected from alkyl having from 1 to 4 carbon atoms.
Accordingly, as used herein, alkyl is especially C,-C4-alkyl, e.g. n-butyl, sec-butyl, tert-butyl, n-propyl, isopropyl, or especially methyl or also ethyl.
In a more preferred aspect R1 is Ci-alkyl e.g. methyl.
More particularly the present invention pertains to a compound selected from the group consisting of compound of formula I and compound of formula II, N w NCH
The present present invention pertains to a compound selected from the group consisting of compound of formula la, R
N-CH3 Ia HO_ ~ ~ H
Wherein A and Q are each H or form together an additional bond, and wherein the asymmetric center in position 3 may be racemic, or in form of an optically active form, and wherein R is of formula Ib or Ic, N ~ N~R1 Ib S N Ic N
and wherein R1 is alkyl, in free base or acid addition salt form.
In a preferred aspect A and Q are each H. In a further preferred aspect A and Q form together an additional bond.
The substituent CH2-R in position 3 of formula la is preferably in configuration 3R, provided A and Q are each H.
R1 is preferably selected from alkyl having from 1 to 4 carbon atoms.
Accordingly, as used herein, alkyl is especially C,-C4-alkyl, e.g. n-butyl, sec-butyl, tert-butyl, n-propyl, isopropyl, or especially methyl or also ethyl.
In a more preferred aspect R1 is Ci-alkyl e.g. methyl.
More particularly the present invention pertains to a compound selected from the group consisting of compound of formula I and compound of formula II, N w NCH
S S S N
N
HO ~ t II
wherein the CH2-S-imidazol substituent in formula I presents the configuration 3R, in free base or acid addition salt form.
An even more preferred aspect of the present invention is a compound of formula I as defined above. Also highly preferred is a compound of formula II as defined above.
Acid addition salts may be produced from the free bases in known manner, and vice versa.
Suitable acid addition salts for use in accordance with the present invention include for example the hydrochloride.
The compounds of formula la, I and II and their physiologically acceptable acid addition salts, referred to hereinafter as compounds of the invention, exhibit valuable pharmacological properties in animal tests and are therefore useful as pharmaceuticals.
Prior art:
The compounds of the present invention exhibit favorable pharmacological properties vis-a-vis the closest prior art, e.g. EP 912'553.
Detailed descriction of the present invention:
In particular, the compounds according to the invention produce a decrease on the intraocular pressure (IOP) in rabbits, at concentrations of 10 to 100 uM. Male rabbits of ca.
2.5 kg are fixed in cages leaving their heads free. The solutions with the compound to be tested are applied to the right eye and the placebo solutions to the left eye (2 drops each, i.e.
ca. 40u1). The eyes are firstly anaesthetized with a solution containing Novesine (0.4 %) and Fluorescein (0.05 %) and the ocular pressure is determined at various intervals after administration (10, 20, 30, 60, 90, 120, 180 and 240 minutes), whereby an applanation tonometer according to Goldberg is used.
Surprisingly, the compounds according to the invention exhibit a strong IOP-lowering efficacy, an excellent tolerability, and a long duration of action, and are therefore in particular useful in the treatment of glaucoma and myopia. In a preferred aspect it refers to the treatment of glaucoma.
For the above mentioned indication, the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about 10 mg/kg animal body weight. In larger mammals, for example humans , an indicated daily dosage is in the range from about 5 to about 200 mg, preferably about 10 to about 100 mg of the compound conveniently administered in divided doses up to 4 times a day or in sustained release form.
The compounds of the invention may be administered in free form or in pharmaceutically acceptable salt form. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
Accordingly the present invention provides a compound of the invention for use as a pharmaceutical, e.g. in the treatment of glaucoma and myopia.
The present invention furthermore provides a pharmaceutical composition comprising a compound of the invention in association with at least one pharmaceutically acceptable diluent or carrier. Such compositions may be formulated in conventional manner. Unit dosage forms contain, for example, from about 0.25 to about 50 mg of a compound according to the invention.
Compounds according to the invention may be administered by any conventional route, for example parenterally e.g. in form of injectable solutions or suspensions, or enterally, preferably orally, e.g. in the form of tablets or capsules.
More preferably, they are applied topically to the eye in ca. 0.002 to 0.02 %
ophthalmological solutions.
The ophthalmic vehicle is such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye.
The pharmaceutically acceptable ophthalmic vehicle may be e.g. an ointment, vegetable oil, or an encapsulating material.
In accordance with the foregoing, the present invention also provides a compound of the invention for use as a pharmaceutical in the treatment of glaucoma and myopia.
Moreover the present invention provides the use of a compound of the invention, for the manufacture of a medicament for the treatment of glaucoma and myopia.
In still a further aspect the present invention provides a method for the treatment of glaucoma and myopia in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound of the invention.
Example 1:
j3R.4aR,1 OaRI-1-methyl-3~i-hydrox~yl-6-methoxy-1,2,3.4. 4aa,5.10, 10a13-octahydrobenzofalauinoline To a solution of 5.78g (20 mM) [3R,4aR,10aR]-1-methyl-3~3-methoxycarbonyl-6-methoxy-1,2,3,4,4aa,5,10,10a~i-octahydrobenzo[g]quinoline in 100 ml toluene, a solution of 12 ml SDBA (sodium dihydro-bis-(2-mthoxyethoxy) aluminate) (70 % in toluene, 42 mM) are added in drops under argon at room temperature within one hour. Then 10 ml NaOH (30 %) are added in drops to the ice cooled reaction mixture. The precipitated crystals are filtered off, washed with water and toluene and dried. The resulting title compound has a m.p. of 148°;
[a]2°p= -120° (c = 0.425 in ethanol).
Example 2 f3R 4aR.10aR1-1-methyl-3[3-mesyloxymethyl-6-methoxy-1.2,3.4,4aa,5,10, 1 Oa~3-octahydrobenzof ql_G.uinoline 12 ml (153 mM) methanesulfochloride are added in drops to a solution of 20 g (76.5 mM) of the compound obtained under example 1 in 150 ml pyridine at room temperature.
The temperature is kept below 45° by ice cooling. After stirring for 2 hours at room temperature, the solution is adjusted to pH 7-8 with saturated KHC03 solution at 0°
and extracted with ethylacefate. After drying over Na2S04, filtering and concentrating by evaporation, the title compound is obtained as beige crystals and directly used for the next step.
Example 3 A solution of 2 g (5.9 mmol) of the mesylate, as obtained in example 2, ands g (8.8 mM) 1-methyl-2-mercapto-imidazole in 30 ml dimethlyformamide are mixed with 2 ml 10 N NaOH
and stirred at 60°C for 3 hours. The resulting suspension is concentrated by evaporation under vacuum and is then extracted with ethylacetate / isopropanol (9:1 ).
After drying over Na2 S04, filtration, and removing of the solvent under vacuum, the methyl ether of the compound of formula I is obtained, which is then directly used for the next step.
Example 4 => compound of formula I:
To a solution of 1.76 g (5 mmol) of the compound obtained in example 1 in 10 ml methylenechloride, 25 ml boron tribromide (1 molar in methylenechloride) are slowly added in drops at a temperature of - 50°C. The suspension is stirred for 3 hours at room temperature, neutralized with aqueous ammonia and extracted with ethylacetate /
isopropanol (9:1 ). The extract is dried over sodium sulfate, filtered and the solvent removed under vacuum. An excess amount of hydrochloric acid in methanol is added, until pH=1 is reached. The solvent is then gradually removed until crystallization occurs.
The hydrochloride is re-crystallized from methanol / ethanol (1:1 ), m.p. 272-274°C. ape°= -38°
(c=0.375 in ethanol / water). Ci9H25N3OS (2 HCI), MW = 416.4.
Example 5:
N
HO ~ t II
wherein the CH2-S-imidazol substituent in formula I presents the configuration 3R, in free base or acid addition salt form.
An even more preferred aspect of the present invention is a compound of formula I as defined above. Also highly preferred is a compound of formula II as defined above.
Acid addition salts may be produced from the free bases in known manner, and vice versa.
Suitable acid addition salts for use in accordance with the present invention include for example the hydrochloride.
The compounds of formula la, I and II and their physiologically acceptable acid addition salts, referred to hereinafter as compounds of the invention, exhibit valuable pharmacological properties in animal tests and are therefore useful as pharmaceuticals.
Prior art:
The compounds of the present invention exhibit favorable pharmacological properties vis-a-vis the closest prior art, e.g. EP 912'553.
Detailed descriction of the present invention:
In particular, the compounds according to the invention produce a decrease on the intraocular pressure (IOP) in rabbits, at concentrations of 10 to 100 uM. Male rabbits of ca.
2.5 kg are fixed in cages leaving their heads free. The solutions with the compound to be tested are applied to the right eye and the placebo solutions to the left eye (2 drops each, i.e.
ca. 40u1). The eyes are firstly anaesthetized with a solution containing Novesine (0.4 %) and Fluorescein (0.05 %) and the ocular pressure is determined at various intervals after administration (10, 20, 30, 60, 90, 120, 180 and 240 minutes), whereby an applanation tonometer according to Goldberg is used.
Surprisingly, the compounds according to the invention exhibit a strong IOP-lowering efficacy, an excellent tolerability, and a long duration of action, and are therefore in particular useful in the treatment of glaucoma and myopia. In a preferred aspect it refers to the treatment of glaucoma.
For the above mentioned indication, the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about 10 mg/kg animal body weight. In larger mammals, for example humans , an indicated daily dosage is in the range from about 5 to about 200 mg, preferably about 10 to about 100 mg of the compound conveniently administered in divided doses up to 4 times a day or in sustained release form.
The compounds of the invention may be administered in free form or in pharmaceutically acceptable salt form. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
Accordingly the present invention provides a compound of the invention for use as a pharmaceutical, e.g. in the treatment of glaucoma and myopia.
The present invention furthermore provides a pharmaceutical composition comprising a compound of the invention in association with at least one pharmaceutically acceptable diluent or carrier. Such compositions may be formulated in conventional manner. Unit dosage forms contain, for example, from about 0.25 to about 50 mg of a compound according to the invention.
Compounds according to the invention may be administered by any conventional route, for example parenterally e.g. in form of injectable solutions or suspensions, or enterally, preferably orally, e.g. in the form of tablets or capsules.
More preferably, they are applied topically to the eye in ca. 0.002 to 0.02 %
ophthalmological solutions.
The ophthalmic vehicle is such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye.
The pharmaceutically acceptable ophthalmic vehicle may be e.g. an ointment, vegetable oil, or an encapsulating material.
In accordance with the foregoing, the present invention also provides a compound of the invention for use as a pharmaceutical in the treatment of glaucoma and myopia.
Moreover the present invention provides the use of a compound of the invention, for the manufacture of a medicament for the treatment of glaucoma and myopia.
In still a further aspect the present invention provides a method for the treatment of glaucoma and myopia in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound of the invention.
Example 1:
j3R.4aR,1 OaRI-1-methyl-3~i-hydrox~yl-6-methoxy-1,2,3.4. 4aa,5.10, 10a13-octahydrobenzofalauinoline To a solution of 5.78g (20 mM) [3R,4aR,10aR]-1-methyl-3~3-methoxycarbonyl-6-methoxy-1,2,3,4,4aa,5,10,10a~i-octahydrobenzo[g]quinoline in 100 ml toluene, a solution of 12 ml SDBA (sodium dihydro-bis-(2-mthoxyethoxy) aluminate) (70 % in toluene, 42 mM) are added in drops under argon at room temperature within one hour. Then 10 ml NaOH (30 %) are added in drops to the ice cooled reaction mixture. The precipitated crystals are filtered off, washed with water and toluene and dried. The resulting title compound has a m.p. of 148°;
[a]2°p= -120° (c = 0.425 in ethanol).
Example 2 f3R 4aR.10aR1-1-methyl-3[3-mesyloxymethyl-6-methoxy-1.2,3.4,4aa,5,10, 1 Oa~3-octahydrobenzof ql_G.uinoline 12 ml (153 mM) methanesulfochloride are added in drops to a solution of 20 g (76.5 mM) of the compound obtained under example 1 in 150 ml pyridine at room temperature.
The temperature is kept below 45° by ice cooling. After stirring for 2 hours at room temperature, the solution is adjusted to pH 7-8 with saturated KHC03 solution at 0°
and extracted with ethylacefate. After drying over Na2S04, filtering and concentrating by evaporation, the title compound is obtained as beige crystals and directly used for the next step.
Example 3 A solution of 2 g (5.9 mmol) of the mesylate, as obtained in example 2, ands g (8.8 mM) 1-methyl-2-mercapto-imidazole in 30 ml dimethlyformamide are mixed with 2 ml 10 N NaOH
and stirred at 60°C for 3 hours. The resulting suspension is concentrated by evaporation under vacuum and is then extracted with ethylacetate / isopropanol (9:1 ).
After drying over Na2 S04, filtration, and removing of the solvent under vacuum, the methyl ether of the compound of formula I is obtained, which is then directly used for the next step.
Example 4 => compound of formula I:
To a solution of 1.76 g (5 mmol) of the compound obtained in example 1 in 10 ml methylenechloride, 25 ml boron tribromide (1 molar in methylenechloride) are slowly added in drops at a temperature of - 50°C. The suspension is stirred for 3 hours at room temperature, neutralized with aqueous ammonia and extracted with ethylacetate /
isopropanol (9:1 ). The extract is dried over sodium sulfate, filtered and the solvent removed under vacuum. An excess amount of hydrochloric acid in methanol is added, until pH=1 is reached. The solvent is then gradually removed until crystallization occurs.
The hydrochloride is re-crystallized from methanol / ethanol (1:1 ), m.p. 272-274°C. ape°= -38°
(c=0.375 in ethanol / water). Ci9H25N3OS (2 HCI), MW = 416.4.
Example 5:
To a solution of 4 g (15.4 mM) of 1,2,4aS-trans-5,10,10a-hexahydro-6-methoxy-1-methyl-3-hydroxymethyl-benzo[g]quinoline (see Registry No. 201869-32-1, Chem. Abstr.) in 40 ml toluene, 1.3 ml (17.9 mM) thionylchloride are slowly added dropwise at a temperature of 0°C.
The suspension is stirred for 12 hours at room temperature. The resulting chloride crystallizes spontaneously. After filtration and washing with toluene, the product is directly used in the next step.
Example 6:
To a solution of 4 g (17.6 mM) of the chloride as obtained in example 5 in 100 ml dichloromethane, 50.5 ml 1 molar boron tribromide in dichloromethane are slowly added at -70°C. The suspension is stirred for 3 hours at room temperature, neutralized with NaHC03 and extracted with ethylacetate / isopropanol (9:1 ). After drying over Na2S04, filtering and concentration by evaporation, the corresponding 6-hydroxy-benzo[g]quinoline derivative is directly used in the next step.
Example 7 => (Compound of formula II) A solution of 930 mg (3.5 mM) of the 6-hydroxy-benzo[g]quinoline derivative of example 6 and 705 mg (4.2 mM) thiazolo[4,5-b]pyridine-2-thiol in 30 ml dimethylformamide is mixed with 10N NaOH and stirred at room temperature for 1 hour. The resulting suspension is concentrated by evaporation under vacuum and is then extracted with ethylacetate /
isopropanol (9:1 ). After drying over Na2 S04, filtration, and removing of the solvent under vacuum, the resulting residue is chromatographed over silica using dichloromethane /
ethylacetate / methanol in a ratio of 40:55:5. The purified material is then converted into the hydrochloride by adding HCI in ethanol and subsequent evaporation. Re-crystallization from methanol/ethanol furnished the compound of formula II as hydrochloride, with a m.p. of 240°C (decomp.), ape°= - 101 ° (c=0.405 in ethanol /
water). C21H~1N3OS2 (HCI), MW =
432.01.
The suspension is stirred for 12 hours at room temperature. The resulting chloride crystallizes spontaneously. After filtration and washing with toluene, the product is directly used in the next step.
Example 6:
To a solution of 4 g (17.6 mM) of the chloride as obtained in example 5 in 100 ml dichloromethane, 50.5 ml 1 molar boron tribromide in dichloromethane are slowly added at -70°C. The suspension is stirred for 3 hours at room temperature, neutralized with NaHC03 and extracted with ethylacetate / isopropanol (9:1 ). After drying over Na2S04, filtering and concentration by evaporation, the corresponding 6-hydroxy-benzo[g]quinoline derivative is directly used in the next step.
Example 7 => (Compound of formula II) A solution of 930 mg (3.5 mM) of the 6-hydroxy-benzo[g]quinoline derivative of example 6 and 705 mg (4.2 mM) thiazolo[4,5-b]pyridine-2-thiol in 30 ml dimethylformamide is mixed with 10N NaOH and stirred at room temperature for 1 hour. The resulting suspension is concentrated by evaporation under vacuum and is then extracted with ethylacetate /
isopropanol (9:1 ). After drying over Na2 S04, filtration, and removing of the solvent under vacuum, the resulting residue is chromatographed over silica using dichloromethane /
ethylacetate / methanol in a ratio of 40:55:5. The purified material is then converted into the hydrochloride by adding HCI in ethanol and subsequent evaporation. Re-crystallization from methanol/ethanol furnished the compound of formula II as hydrochloride, with a m.p. of 240°C (decomp.), ape°= - 101 ° (c=0.405 in ethanol /
water). C21H~1N3OS2 (HCI), MW =
432.01.
Claims (7)
1. A compound of formula I, wherein the CH2-S-imidazol substituent in formula I presents the configuration 3R, in free base or acid addition salt form.
2. A pharmaceutical composition comprising a compound of claim 1 in free base or acid addition salt form and at least one pharmaceutically acceptable diluent or carrier.
3. The compound of claim 1 in free base or acid addition salt form for use as a pharmaceutical.
4. The compound of claim 1 in free base or acid addition salt form for use as a pharmaceutical in the treatment of glaucoma or myopia.
5. Use of a compound of claim 1 in free base or acid addition salt form, for the manufacture of a medicament for the treatment of glaucoma or myopia.
6. Use of a compound of claim 1 in free base or acid addition salt form, for the treatment of glaucoma or myopia.
7. The pharmaceutical composition according to claim 2 for use in the treatment of glaucoma or myopia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2706618A CA2706618A1 (en) | 2002-03-07 | 2003-03-06 | Quinoline derivatives |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP02005115.7 | 2002-03-07 | ||
| EP02005117 | 2002-03-07 | ||
| EP02005115 | 2002-03-07 | ||
| EP02005117.3 | 2002-03-07 | ||
| PCT/EP2003/002321 WO2003074511A1 (en) | 2002-03-07 | 2003-03-06 | Quinoline derivatives |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2706618A Division CA2706618A1 (en) | 2002-03-07 | 2003-03-06 | Quinoline derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2477720A1 CA2477720A1 (en) | 2003-09-12 |
| CA2477720C true CA2477720C (en) | 2010-09-21 |
Family
ID=27790094
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2477720A Expired - Fee Related CA2477720C (en) | 2002-03-07 | 2003-03-06 | Quinoline derivatives |
| CA2706618A Abandoned CA2706618A1 (en) | 2002-03-07 | 2003-03-06 | Quinoline derivatives |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2706618A Abandoned CA2706618A1 (en) | 2002-03-07 | 2003-03-06 | Quinoline derivatives |
Country Status (29)
| Country | Link |
|---|---|
| US (2) | US7399768B2 (en) |
| EP (1) | EP1480970B1 (en) |
| JP (2) | JP2005519117A (en) |
| KR (1) | KR101027977B1 (en) |
| CN (2) | CN1939915A (en) |
| AR (1) | AR038730A1 (en) |
| AU (1) | AU2003219023B2 (en) |
| BR (1) | BR0308201A (en) |
| CA (2) | CA2477720C (en) |
| CO (1) | CO5611196A2 (en) |
| CY (1) | CY1106409T1 (en) |
| DE (1) | DE60311233T2 (en) |
| DK (1) | DK1480970T3 (en) |
| EC (1) | ECSP045271A (en) |
| EG (1) | EG24415A (en) |
| ES (1) | ES2279100T3 (en) |
| HK (1) | HK1071364A1 (en) |
| IL (1) | IL163769A0 (en) |
| MX (1) | MXPA04008666A (en) |
| MY (1) | MY134325A (en) |
| NO (1) | NO20044117L (en) |
| NZ (1) | NZ534732A (en) |
| PE (1) | PE20030927A1 (en) |
| PL (2) | PL210336B1 (en) |
| PT (1) | PT1480970E (en) |
| RU (1) | RU2345991C2 (en) |
| SI (1) | SI1480970T1 (en) |
| TW (1) | TW200406401A (en) |
| WO (1) | WO2003074511A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1757601B1 (en) * | 2002-03-07 | 2009-08-05 | Novartis AG | Quinoline derivatives and their use in glaucoma and myopia |
| PE20211290A1 (en) | 2017-11-24 | 2021-07-20 | H Lundbeck As | NEW CATECOLAMINE PROPHARMACS FOR USE IN THE TREATMENT OF PARKINSON'S DISEASE |
| US11168056B2 (en) | 2019-05-20 | 2021-11-09 | H. Lundbeck A/S | Process for the manufacturing of (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4′,5′:5,6]benzo[1,2-G]quinoline and (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[G]quinoline-6,7-diol |
| US11111263B2 (en) | 2019-05-20 | 2021-09-07 | H. Lundbeck A/S | Process for the manufacture of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid |
| US11130775B2 (en) | 2019-05-20 | 2021-09-28 | H. Lundbeck A/S | Solid forms of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4A,5,10,10A-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid |
| US11104697B2 (en) | 2019-05-20 | 2021-08-31 | H. Lundbeck A/S | Process for the manufacture of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4AR,10AR)-7-hydroxy-1- propyl-1,2,3,4,4A,5,10,10A-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL100555A (en) * | 1991-02-07 | 2000-08-31 | Hoechst Marion Roussel Inc | N-substituted quinoline derivatives their preparation their use for the preparation of medicaments and the pharmaceutical compositions containing them |
| GB9326010D0 (en) * | 1993-12-21 | 1994-02-23 | Sandoz Ltd | Improvements in or relating to organic compounds |
| TW378209B (en) * | 1996-07-08 | 2000-01-01 | Novartis Ag | Benzo[g]quinoline derivatives, their preparation and the pharmaceutical composition containing them |
| PE20030240A1 (en) * | 2001-07-09 | 2003-04-16 | Novartis Ag | BENZO DERIVATIVES [g] QUINOLINE |
-
2003
- 2003-03-03 EG EG2003030215A patent/EG24415A/en active
- 2003-03-05 PE PE2003000212A patent/PE20030927A1/en not_active Application Discontinuation
- 2003-03-05 TW TW092104671A patent/TW200406401A/en unknown
- 2003-03-05 AR ARP030100740A patent/AR038730A1/en unknown
- 2003-03-06 CN CNA2006101357990A patent/CN1939915A/en active Pending
- 2003-03-06 CN CNB038053608A patent/CN1293070C/en not_active Expired - Fee Related
- 2003-03-06 PT PT03714784T patent/PT1480970E/en unknown
- 2003-03-06 DK DK03714784T patent/DK1480970T3/en active
- 2003-03-06 CA CA2477720A patent/CA2477720C/en not_active Expired - Fee Related
- 2003-03-06 US US10/506,232 patent/US7399768B2/en not_active Expired - Fee Related
- 2003-03-06 MX MXPA04008666A patent/MXPA04008666A/en active IP Right Grant
- 2003-03-06 WO PCT/EP2003/002321 patent/WO2003074511A1/en active IP Right Grant
- 2003-03-06 EP EP03714784A patent/EP1480970B1/en not_active Expired - Lifetime
- 2003-03-06 PL PL370915A patent/PL210336B1/en unknown
- 2003-03-06 KR KR1020047012409A patent/KR101027977B1/en not_active IP Right Cessation
- 2003-03-06 BR BR0308201-6A patent/BR0308201A/en not_active Application Discontinuation
- 2003-03-06 RU RU2004129767/04A patent/RU2345991C2/en not_active IP Right Cessation
- 2003-03-06 JP JP2003572979A patent/JP2005519117A/en active Pending
- 2003-03-06 IL IL16376903A patent/IL163769A0/en unknown
- 2003-03-06 ES ES03714784T patent/ES2279100T3/en not_active Expired - Lifetime
- 2003-03-06 SI SI200330755T patent/SI1480970T1/en unknown
- 2003-03-06 NZ NZ534732A patent/NZ534732A/en unknown
- 2003-03-06 CA CA2706618A patent/CA2706618A1/en not_active Abandoned
- 2003-03-06 AU AU2003219023A patent/AU2003219023B2/en not_active Ceased
- 2003-03-06 DE DE60311233T patent/DE60311233T2/en not_active Expired - Lifetime
- 2003-03-06 PL PL394208A patent/PL215012B1/en unknown
- 2003-03-07 MY MYPI20030808A patent/MY134325A/en unknown
-
2004
- 2004-09-02 EC EC2004005271A patent/ECSP045271A/en unknown
- 2004-09-15 CO CO04091781A patent/CO5611196A2/en not_active Application Discontinuation
- 2004-09-28 NO NO20044117A patent/NO20044117L/en not_active Application Discontinuation
-
2005
- 2005-05-17 HK HK05104122A patent/HK1071364A1/en not_active IP Right Cessation
-
2007
- 2007-03-22 CY CY20071100405T patent/CY1106409T1/en unknown
-
2008
- 2008-06-12 US US12/137,819 patent/US20080255176A1/en not_active Abandoned
-
2010
- 2010-02-04 JP JP2010022863A patent/JP2010095550A/en active Pending
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20080255176A1 (en) | Quinoline derivatives | |
| JP2010024243A (en) | Benzo[g]quinoline derivative for treatment of glaucoma and myopia | |
| AU2002328856A1 (en) | Benzo (G) quinoline derivatives for treating glaucoma and myopia | |
| US6057334A (en) | Benzo[g]quinoline derivatives | |
| EP1757601A1 (en) | Quinoline derivatives and their use in glaucoma and myopia |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20160307 |